PROJECT DESCRIPTION Multiple sclerosis (MS) is one of the most disabling neuro-inflammatory disorders that affects the brain and spinal cord. Around 400,000 people are living with MS in the United States and approximately 2.1 million individuals worldwide suffer from this condition. The exact mechanism that drives MS is not entirely understood. However, the condition is generally thought as an autoimmune disease that attacks the myelin sheath in the brain and spinal cord, which functions as the protective layer surrounding the nerves in the central nerve system that help electrical signals to transmit from the brain to the rest of the body. Once deteriorated, the disease can permanently damage the nerves, leading to loss of ability to walk. At present, there is no cure for MS, and disease-modifying therapies are among the limited treatment options. Thus, new therapy is urgently needed for effective treatment of MS. From our recent study, we have discovered novel small-molecule chemical agents that favor lineage differentiation of oligodendrocytes, a key step for myelin repair. Our lead compounds can inhibit over-development of pro-inflammatory Th17 cells in mice, which have recently been recognized as a major driving factor for the pathogenesis of MS. Motivated by our recent discovery, we propose to optimize oral bioavailability and CNS activity, and validate the therapeutic potential of our novel chemical epigenetic modulators as new effective treatment for MS, as outlined in two Specific Aims of this project. The results from this Phase I study will prepare us for a more efficient Phase II study of an extensive pre-clinical evaluation of our most promising drug candidates for MS in human clinical trials.